RESEARCH ARTICLE A Functional Cancer Genomics Screen Identifi es a Druggable Synthetic Lethal Interaction between MSH3 and PRKDC

ABSTRACT Here, we use a large-scale cell line–based approach to identify cancer cell–specifi c mutations that are associated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) dependence. For this purpose, we profi led the mutational landscape across 1,319 cancer-associated genes of 67 distinct cell lines and identifi ed numerous genes involved in homologous recombi-nation–mediated DNA repair, including BRCA1, BRCA2, ATM, PAXIP, and RAD50, as being associated with non-oncogene addiction to DNA-PKcs. Mutations in the mismatch repair gene MSH3, which have been reported to occur recurrently in numerous human cancer entities, emerged as the most signifi cant pre-dictors of DNA-PKcs addiction. Concordantly, DNA-PKcs inhibition robustly induced apoptosis in MSH3-mutant cell lines in vitro and displayed remarkable single-agent effi cacy against MSH3-mutant tumors in vivo. Thus, we here identify a therapeutically actionable synthetic lethal interaction between MSH3 and the non-homologous end joining kinase DNA-PKcs. Our observations recommend DNA-PKcs inhibition as a therapeutic concept for the treatment of human cancers displaying homologous recombination defects. SIGNIFICANCE: We associate mutations in the MSH3 gene, which are frequently detected in micro-satellite-instable colon cancer (∼40%), with a therapeutic response to specifi c DNA-PKcs inhibitors. Because potent DNA-PKcs inhibitors are currently entering early clinical trials, we offer a novel oppor-tunity to genetically stratify patients who may benefi t from a DNA-PKcs–inhibitory therapy. Cance